The term “blister”, herein, signifies a closed pocket or cavity made from opposed deformable thin layers that seal the pocket or cavity. Blisters are commonly used for the packaging of consumer goods, food or pharmaceuticals where they provide protection against external factors such as moisture, UV irradiation and contamination. Most blisters are designed for solid objects, and burst across one of the two large surfaces defined by a thin layer, but a special class of blister is desired for retaining and expressing fluids. The fluid is typically a liquid, a solution, a suspension, an aqueous gel, or a fluidized particulate assembly, and typically includes at least one liquid fraction. Fluids require more control of the release during burst of the blister seal than solids, and may require tighter seals. Specifically, it is desirable to burst fluids along an interface with a microfluidic circuit that guides the fluid in a useful direction.
Blisters have attracted interest as a means of storing fluid (e.g., sample solution, buffer or reagents) on microfluidic chips, offering the prospect of performing sample analysis in a compact and inexpensive format for point-of-care (POC) diagnostics. Ejection of small volumes of fluid from the blister and its displacement within the fluidic system is anticipated to proceed through burst of the blister (e.g., as a result of applying pressure with fingertips). For example, U.S. Pat. No. 9,207,239 teaches a test cartridge for assaying infections, the cartridge having 3 microfluidic blisters that are designed to, when burst, express fluid into a chamber via a microfluidic channel.
US 2011/143,339 to Wisniewski describes a particular problem with microfluidic blisters: prior art devices that make use of temporary or frangible seals to isolate different sealed chambers may be unreliable, particularly when the regions they separate only contain low volumes (e.g., 50 microliters or less). When placing a pressure seal over a blister or channel, a capillary fluid path may remain at the interface between the pressure seal and the heat seal. Even when this capillary flow path only allows a small volume of liquid to pass, the seal is compromised. A small amount of leaked liquid may lead to the unwanted re-hydration of reagents held in adjacent sealed regions. Wisniewski's solution is to use continuously applied external pressure to form the seal. However this solution complicates design of microfluidics, requires higher parts count chips, and registration of multiple components.
It is clear that functioning of a blister requires the presence of a breakable seal that gates the blister. Herein gating is the function that allows for retention of the fluid in the blister and release of the fluid when burst. The blister should also provide an effective barrier against fluid evaporation, contamination, and reaction during storage while remaining sensitive enough to discharge the fluid when and only when a certain threshold pressure impulse is applied to the blister. Although highly desirable, especially for the dispensing of small volumes for diagnostic lab-on-a-chip technology (Hitzbleck & Delamarche, 2013), a satisfactorily functional valve has not yet been achieved. The ability to store small amounts of reagents on micro total analysis systems (μTAS) is an important step towards making “labs on chips”, as opposed to “chips in labs”.
Hitzbleck & Delamarche surveyed the techniques available, and concluded: two main strategies are used currently to tackle the challenge of integrating reagents into microfluidic devices: namely using a more technology-oriented approach; or a physico-chemical approach. They observe that the technological approaches favour tools that deposit reagents during fabrication of the microfluidic device or built a part of the device itself and actively dose reagents during use of the chip, and that these solutions feature high precision (amount, time and space of released reagents) but the devices are complex to manufacture and often involve bulky peripheral equipment. The physico-chemical approach is said to be dominated by beads as carriers for immobilized reagents and hydrogels as scaffolds for sustained release. Physico-chemical solutions enable the preparation and optimization of reagents offchip and in large amounts but the solutions are often specific to a reagent and its desired release profile, and must be adapted on a case by case basis. They conclude that a combination of physico-chemical and technology-oriented approaches has the potential to outperform current approaches both in terms of precision and practicability.
The most frequently used material for producing blisters, is polyvinylchloride (PVC). Other polymers include polychlorotrifluoro ethylene (PCTFE) and cyclic olefin copolymers (COC). There are two principal methods of producing blister packs: thermoforming and cold forming followed by a lamination process (often with adhesive aluminum foil). When used in microfluidic systems, fluid can be pre-incorporated into a designated storage compartment before sealing, or, fluid can be inserted into the system via loading ports after the lamination process.
Disch, Mueller, & Reinecke, 2007 and Focke et al., 2010 have used thermoforming for fabricating blisters with microfluidic components simultaneously on the same substrates. Disch, Mueller & Rienecke teach a multi-step blister made by: forming a polypropylene (PP)-COC-PP laminated film using trapped sheet vacuum thermoforming; applying a liquid into cavities of the formed PP-COC-PP film; and laminating the back of the cavities with the foil (although other plastics are suggested to be options), using an undisclosed lamination process. The lamination of the foil to the formed PP-COC-PP film is expected to be based on deformation of the Al foil as opposed to the PP-COC-PP film. As blister packs for sealing capsules break by tearing of the foil, this leaves some difficulties for releasing the liquid in a contained manner. While FIG. 7 of this reference clearly shows a blister pack with integrated microfluidics, it is far from clear how controlled valving of the liquid from the two blister chambers can be achieved. No technique is explained in the document for dispensing the liquid in one or both chambers, and in fact this would require some kind of valve, which is challenging when using known lamination processes. In order to propagate liquid from a blister cavity, the joint layers must be de-laminated along the pathway, and no access is given to this interface, except through the formed PP-COC-PP film, or the foil. If, unlike conventional blister packaging, the foil or backing material is resistant enough to avoid breakage when the blister is being opened, conventional lamination will not allow for controlled delamination of only the desired parts of the foil. Accordingly, the liquid would be expected to exit the cavity at random locations making it unavailable for an assay. Therefore, further equipment not taught or shown is required to provide for controlled release of a blister pack into a microfluidic channel.
Some closed systems are known. For example, U.S. Pat. No. 5,290,518 to Johnson proposes liquid cavities with thin side walls forming breakable barriers. The arrangement includes two thicker formed sheets sandwiching a thin sheet that is liable to tear or burst in response to pressure applied to the thicker sheets. Containment of the liquid in an opposite chamber is automatic, but some shards or remnants of the thin sheet may need to be removed from the resulting flow, and control over the bursting pressure may deteriorate over time, requiring filters and other additional structures/components. Furthermore, the release of the liquid is unconstrained in 3 dimensions according to Johnson, and the rupture mechanism is generally unpredictable.
Alternative arrangements are known that integrate a piercing element (pin or needle) to break the seal as pressure is applied (Choikhet, 2007; Handique & Kehrer, 2006). Other variants include the use of a prefilled tubular-shaped pack or pouch made from laminated composite foil (van Oordt, Barb, Smetana, Zengerle, & von Stetten, 2013) or thin pre-filled glass ampoules (Hoffmann, Mark, Lutz, Zengerle, & von Stetten, 2010) inserted into a cavity or channel of the microfluidic circuit. Once force is applied (e.g., pressure, centrifugal force), the respective foil or glass cavity is broken thereby releasing the fluid. These variants add to complexity in the design and increase cost of the device, and complexity of the fabrication.
The use of movable membranes (or plugs) to provide an opening in a fluid-containing chamber has also been reported. Under pressure the membrane (or plug) lifts thereby leaving an opening (Boden, Lehto, Margell, Hjort, & Schweitz, 2008). Here, the membrane must be separately installed or inserted into the fabricated microfluidic device which makes it impractical for low-cost, single-use devices.
Applicant's co-pending patent application Pub. No.: US 2013/0139899 entitled SEMIPERMANENTLY CLOSED MICROFLUIDIC VALVE teaches the formation of a semipermanently closed valve in a microfluidic device by providing a patterned thermoplastic elastomer (TPE) that makes a conformal and intimate contact with a hard, smooth surface, and pressing channels closed with nominal pressure and heat, to result in a seal that requires no continuous pressure to retain. At para. [0061], this co-pending patent application addresses the issue of gating as follows: “There are competing requirements for the material deformation and bonding properties that have to be in balance in order to permit the valve to reopen reliably and easily, while ensuring that the bonding is stable until thermomechanical stimulus is encountered.”
It is desirable to maintain better flow control during release of a fluid without complicating fabrication of a blister. The present invention provides a technique for improving the reliability of the gating operation, while avoiding additional material layers and components of the microfluidic chip.